© U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(02)00371-8

Vol. 23 No. 4S April 2002 Journal of Pain and Symptom Management S21

Proceedings from the Symposium “The Evolution of Anti-Inflammatory Treatments in Arthritis: Current and Future Perspectives”

Commentary: Renal Effects of Cyclooxygenase-2-Selective Inhibitors

Matthew R. Weir, MD

Division of Nephrology and Clinical Research Unit, University of Maryland School of Medicine, Baltimore, Maryland, USA

Key Words

COX-2-specific inhibitors, nonsteroidal anti-inflammatory drugs, renal effects,

blood pressure, edema

Introduction

Since the discovery of the first nonselectivenonsteroidal anti-inflammatory drug (NSAID),aspirin, in 1897, physicians have been manag-ing NSAID-induced adverse events, includinggastrointestinal ulceration and bleeding andrenal effects (e.g., renal dysfunction, changesin blood pressure, peripheral edema, and hy-perkalemia). The cyclooxygenase (COX)-2-spe-cific inhibitors (coxibs) were developed as asafer alternative to NSAIDs in patients at riskfor developing gastrointestinal toxicity. How-ever, through inhibition of constitutive COX-2in the kidneys, the production of prostaglan-dins, which are responsible for regulating elec-trolyte and water balance and vascular tone,may be decreased, leading to such renal effectsas sodium and potassium retention, peripheraledema, and acute reversible renal dysfunction.

Comparison of Renal Effects Between Coxibs and Nonselective NSAIDs

Coxibs (i.e., celecoxib and rofecoxib) andnonselective NSAIDs have essentially the same

incidence and degree of alterations in bloodpressure, edema, and reversible renal dysfunc-tion when equivalent (or equieffective) dosesare compared. These changes are modest andbecome more of a clinical issue in patients withrenal or cardiac dysfunction. Most of the renaleffects are a result of “dose-dependent salt sen-sitivity” in which increasing doses of the NSAIDor coxib in the setting of increased dietary saltintake result in increased events.

Numerous studies have been conducted todetermine the difference in renal effects causedby coxibs and NSAIDs. Catella-Lawson and col-leagues

1

found that indomethacin, when ad-ministered as a 50-mg dose 3 times daily fortwo weeks, caused a modest but significant de-crease (

�

10%) in glomerular filtration rate(GFR) compared with rofecoxib 50 mg daily(

P

�

0.004) or placebo (

P

�

0.014). Rofecoxibwas associated with a decrease in urinary sodiumexcretion that returned to baseline after 72hours of therapy, whereas sodium excretion re-mained slightly decreased in patients treatedwith indomethacin. There were no significantincreases in blood pressure or weight in anytreatment group. The results of this study dem-onstrated that rofecoxib and indomethacin didnot cause clinically significant alterations in re-nal function or blood pressure in older patientswho had normal dietary salt intake.

Likewise, Whelton and associates

2

found thatnaproxen 500 mg twice daily (BID) for 10 days

Address correspondence to:

Matthew R. Weir, MD, Di-rector, Division of Nephrology, University of Mary-land Hospital, 22 South Greene Street, N3W143,Baltimore, Maryland 21201-1595, USA.

Accepted for publication: November 19, 2001.

S22 Weir Vol. 23 No. 4S April 2002

was associated with a transient, statistically sig-nificant (

P

�

0.004), but not clinically signifi-cant, decrease in GFR compared with cele-coxib (200 mg BID for 5 days followed by 400mg BID for 5 days) in healthy older adults. Asin the previous study,

1

urinary sodium ex-cretion decreased slightly in both treatmentgroups, but was not considered to be of clinicalsignificance.

Other investigators

3,4

have demonstrated thatCOX-2-mediated prostaglandins play a role inthe regulation of renal hemodynamics and fluidand electrolyte balance in sodium-restricted pa-tients. Although in all studies urinary sodiumand potassium excretion tended to be de-creased in patients who received either anNSAID or coxib compared with patients whoreceived placebo, the differences were not clin-ically significant. The results of these studiesshow that inhibition of COX-2 was not associ-ated with a clinically significant increase inblood pressure in sodium-restricted patients.

Not enough clinical trials have been per-formed in patients at higher risk for nonsteroi-dal renal syndromes (i.e., patients with cardiacor renal disease). Consequently, data for possi-ble differences between NSAIDs or coxibs arenot available. It is clinically appropriate inthese patients to use the lowest possible dosesto alleviate pain and inflammation, encouragedietary salt reduction, and follow weight, bloodpressure, and laboratory measurements of elec-trolyte and renal function.

Evaluation of Renal Effects with Rofecoxib and Celecoxib

A review of the clinical data with celecoxiband rofecoxib indicates similar, modest alter-ations in prostaglandin secretion, GFR, sodiumreabsorption, and potassium secretion that areof limited clinical significance.

To date, no head-to-head studies have beenspecifically conducted to determine the dif-ference in changes in renal function, bloodpressure, or weight between therapeuticallyequivalent doses of celecoxib and rofecoxib.Moreover, these studies are difficult to per-form because they need to adjust for dose ofdrug and concurrent sodium intake. A recentstudy

5

reported that patients with osteoporosisreceiving rofecoxib 12.5 mg once daily (QD)

or 25 mg QD, or celecoxib 200 mg QD for 6weeks, did not experience clinically significantdifferences in blood pressure, weight, renalfunction, or lower-extremity edema. In addi-tion, the differences were comparable to thoseexperienced by patients who received acetamin-ophen 1000 mg 4 times daily.

To objectively measure differences betweencelecoxib and rofecoxib, or between coxibsand traditional NSAIDs, dose-response clinicaltrials that include patients at high risk for thedevelopment of coxib- or NSAID-induced re-nal dysfunction (e.g., the elderly, or those withvolume depletion, diabetes, congestive heartfailure, hepatic or renal dysfunction, or uncon-trolled hypertension) or with advanced renalinsufficiency need to be conducted. Moreover,dietary sodium needs to be quantitated, anddata adjusted for appropriately. Methodologiessuch as ambulatory blood pressure monitoringover a period of 24 hours, or water-displace-ment measurements to assess for pedal edema,need to be employed. However, because thepercentage of patients who experience NSAID-induced renal effects is relatively small, andsuch trials are complex, they may not providedefinitive answers. The fact that renal effectsare predictable, and are most often observed inhigh-risk patients rather than otherwise healthypatients, may make such trials unnecessary, un-less clinically significant changes are shown tooccur, which could modify clinical approachesto pain control in higher-risk patients.

Patients at Risk andClinical Management

It has been demonstrated that NSAID-inducedrenal effects are particularly worrisome in pa-tients with risk factors such as diabetes, conges-tive heart failure, volume depletion, liver or re-nal disease, or poorly controlled hypertension.Blood pressure changes in normotensive pa-tients treated with coxibs and nonselectiveNSAIDs are usually not clinically significant.

The degree of renal impairment at which anNSAID or coxib should not be prescribed hasbeen debated. Patients with creatinine clearance(CrCl) of less than 30 mL/min should not beprescribed coxibs or NSAIDs because the level ofrenal impairment is significant and could be fur-ther compromised. Unfortunately, few data are

Vol. 23 No. 4S April 2002 Commentary: Renal Effects of Coxibs S23

available in these higher-risk patients to provideaccurate recommendations. Most importantly,adjustments to other medications (e.g., antihy-pertensives) in the patient’s treatment regimenmay need to be made to compensate for additionof the coxib or NSAID for pain relief. Even pa-tients with CrCl of approximately 50 mL/minmay need to be monitored more closely, particu-larly if there are significant changes in serum po-tassium or blood pressure.

Conclusions

Because COX-2 is constitutively expressed inthe kidney, drugs that selectively inhibit COX-2affect renal function in a manner similar tononselective NSAIDs. Several studies have beenconducted to determine whether there is a dif-ference in renal effects caused by coxibs andNSAIDs, but because these studies involved alimited number of patients and employed dif-ferent study designs and end points, compara-tive analyses may not generate accurate results.Moreover, differences in doses and concurrentsodium intake also can substantially alter clini-cal observation. Clinical significance, ratherthan statistical significance, should be the basisfor therapeutic decisions. Currently availabledata suggest that celecoxib and rofecoxib causesodium retention and a decrease in GFR in pa-tients at risk for developing NSAID-induced re-nal effects. Therefore, the same precautions

that apply to use of nonselective NSAIDs shouldbe applied to use of selective COX-2 inhibitors.The lack of comparative dose-response studiesmakes the clinical interpretation of renal ef-fects caused by the two currently available cox-ibs, celecoxib and rofecoxib, difficult. Whetherfuture clinical trials or newer coxibs will demon-strate clinically significant differences in renal ef-fects between coxibs and NSAIDs, or betweendifferent coxibs, remains to be determined.

References

1. Catella-Lawson F, McAdam B, Morrison BW, et al.Effects of specific inhibition of cyclooxygenase-2on sodium balance, hemodynamics, and vasoactiveeicosanoids. J Pharmacol Exp Ther 1999;289:735–741.

2. Whelton A, Schulman G, Wallemark C, et al. Ef-fects of celecoxib and naproxen on renal functionin the elderly. Arch Intern Med 2000;160:1465–1470.

3. Rossat J, Maillard M, Nussberger J, et al. Renal ef-fects of selective cyclooxygenase-2 inhibition in nor-motensive salt-depleted subjects. Clin PharmacolTher 1999;66:76–84.

4. Swan SK, Rudy DW, Lasseter KC, et al. Effect ofcyclooxygenase-2 inhibition on renal function in el-derly persons receiving a low-salt diet. Ann InternMed 2000;133:1–9.

5. Geba GP, Weaver AL, Schnitzer TJ, et al. A com-parison of rofecoxib to celecoxib and acetamin-ophen in the treatment of osteoarthritis [abstract].Arthritis Rheum 2000;43(suppl 9):S384.